PROJECT SUMMARY/ABSTRACT (OVERALL) The overall research goal of this Program Project Grant is to develop the knowledge base and the experimental and theoretical framework for engineering transmissible health. Since the establishment of the germ theory of disease in the late 1800s, a major public health goal has been to limit the transmission of disease-causing microbes. Microbes normally resident in hosts, in contrast, are increasingly appreciated for their health- promoting roles, which include fostering normal development, establishing appropriate immunological tone, and preventing invasion of pathogens. The potential for resident microbes to be used as therapeutic probiotics holds great promise, but current probiotic design strategies focus exclusively on administering probiotics to individual hosts, neglecting the possibility of transmission except as a threat that needs to be prevented. However, just as for pathogens, transmission of commensal microbiota between individuals and within social groups is likely to occur and may even contribute to the health benefits associated with social connectivity. In contrast, microbial isolation is a defining feature of modernized societies, which are experiencing alarming increases in autoimmune disorders and other diseases of microbiota dysbiosis. The interactions between commensal microbes and their environments both within and outside of hosts, and the ways in which these interactions shape dispersal, transmission, and host health, remain opaque, preventing design of community- level strategies to exploit the beneficial potential of our intestinal microbiota. We propose to explore the parameters of inter-host transmission of host-associated bacteria and bacterial communities that could be harnessed for therapeutic purposes. We imagine that the properties of resident bacteria can be tuned to promote health on both an individual and a population level. In particular, we propose to design smart probiotics that would sense and treat inflammation. At a local level, in individual host intestines, these microbes would be engineered to inhibit features of the host environment that favor pro-inflammatory strains. At a population level, these microbes would be engineered to successfully spread between and colonize hosts, and would limit the transmission of pro-inflammatory microbiota members, effectively conferring herd immunity to intestinal inflammation. Our use of zebrafish and their commensal microbiota as an accessible experimental platform for monitoring and manipulating host-microbe systems will provide important new insights that are crucial if we hope to use similar smart probiotic strategies to transform other multi-species systems, such as humans.